In this competing renewal we request five years of support to continue our inquiry into adaptation and health outcomes among Alzheimer caregivers (CG). Our major hypotheses are: 1) that the chronic stress of caregiving will be reflected in physiologic measures of activation - altered hypothalmic-pituitary-adrenal (HPA) axis sensitivity, increased sympathoadrenal medullary (SAM) activity, and reduced natural killer (NK) cell activity; and 2) that over time those CG with highest caregiver stress will show the most significant physiological alterations which will be predictive of worsening CG health. The research is guided by a conceptual model which postulates that to understand the effect of stressors on CG health we must consider the influence of certain mediators and background characteristics. Stressors can be patient-derived (dementia, problem behaviors, help required) or environmental (life events) leading to CG role overload. Mediators are interpersonal (supports) and intrapersonal (self-concept, coping activity). Background characteristics include age, gender socioeconomic status, and past health. The outcomes of caregiving are conceptualized at 3 levels: physiologic (HPA alteration., SAM activation, NK activity), psychologic (anxiety, depression), and physical (symptoms, illness episodes). The study has two components. In the "field" study 200 spousal CG and 80 noncaregiving controls (NC) will be examined every 6 months for 5 years. Data will be gathered on state and needs of the patient, life stresses, resources, supports, medical events, and psychological state of CG. Blood samples for NK, cortisol, ACTH, norepinephrine, epinephrine and neuropeptide Y will be drawn in the CG home during a blood pressure postural reactivity protocol. Nested in the field study is our 'laboratory' study which will, for the first time, attempt to probe HPA axis sensitivity and SAM activation in CG experiencing varying levels of caregiver stress. Here we shall perform corticotropin releasing factor (CRF) infusion studies, as well as sympathetic reactivity studies with 60 CG and 30 NC "selected" to be free of major medical confounds (including medications). The data from this phase should move caregiver research closer to understanding mechanisms linking caregiver stress, physiological response, and health.